The metabolic syndrome is increasingly prevalent in our society and represents a major risk for vascular disease. This syndrome is characterized by central obesity, insulin resistance, fasting and post-prandial atherogenic dyslipidemia as well as a chronic pro-inflammatory state. Thus, chronic activation of innate immunity and postprandial stress converge on the vasculature in the metabolic syndrome. We use low-level human endotoxemia as a model to examine the impact of adiposity and metabolic syndrome on vascular injury and atherogenic signaling in vivo. We have found that this model provides novel mechanistic insight into human pathophysiology in the metabolic syndrome. In this SCCOR project we propose to extend this work by; (Specific Aim 1) performing a placebo controlled trial of peroxisome proliferator-activated receptor alpha (Fenofibrate) and gamma (Rosiglitazone) agonists and Niacin (collaboration with Project by Rader); (Specific Aim 2) use of placebo-controlled acute highfat meal provocation; and (Specific Aim 3) performing an evoked-phenotype pharmacogenetic study on the endotoxin-mediated vascular injury response. In specific hypothesis-driven studies, we will determine the impact of drugs, diet and genes on endotoxin-related vascular injury pathways including; (a) cytokines and inflammatory molecules, (b) cyclooxygenases (COXs) and vasoactive prostaglandins (PGs), particularly PGD2 (collaboration with Project by Fitzgerald), (c) oxidant stress (utilize the Biomarker Core (Blair), and (d) vasoactive adipokines. Drug, diet and candidate gene related changes in leukocyte, monocyte and adipose gene expression will be integrated with plasma and urinary biomarker responses and will serve to provide mechanistic insights that will complement cell and animal model studies across our SCCOR application. Metabolic syndrome represents our major clinical focus because of the interplay of metabolic and inflammatory signals in the promotion of vascular injury and atherosclerosis in this setting.